Gastric cancer is the second leading cause of cancer-related death worldwide and is strongly linked to chronic inflammation. It has been demonstrated that the polymorphisms of IL-1 are associated with the risk for gastric cancer;however, effective means for the prevention of related gastric cancer remains to be investigated. We have previously generated a HK-ATPase-human IL-1 (hIL-1) transgenic mouse model. The hIL-1 mice developed spontaneous gastric inflammation and progress to gastric cancer. We have also demonstrated that the accumulation and activation of myeloid-derived suppressor cells (MDSCs) are early events for the development of gastric cancer in the hIL-1 mice and MDSCs may be a new target for early prevention of gastric cancer. Curcumin, a bioactive food component with inhibition of NF-kB activation, has been shown to have the potential effects on cancer chemoprevention. However, the preventive effect of curcumin on gastric carcinogenesis and its molecular targets remain to be explored. The objective of this project is to study the preventive effect of curcumin on gastric carcinogenesis in this new hIL-1 mouse model by combination of celecoxib (a COX-2 inhibitor). We hypothesize that curcumin inhibits gastric carcinogenesis through by targeting inhibition of the activation of NF-kB in MDSCs and that celecoxib inhibits COX-2 and PGE2, resulting in inhibition of mobilization of MDSCs. Because the two agents act through different mechanisms, their actions may be synergistic. The hypothesis will be tested through three specific aims. (1) To determine the inhibitory effects of curcumin, celecoxib, and their combination on gastric inflammation and carcinogenesis in the hIL-1 mice. (2) To characterize the effects of curcumin and celecoxib on MDSCs mobilization and activation and elucidate the mechanisms of inhibition of gastric carcinogenesis by these agents in the hIL-1 mice. (3) To investigate the effect of targeting inhibition of MDSCs by curcumin and celecoxib on gastric epithelial cells and epithelium-stroma MDSCs interactions in gastric carcinogenesis. This project may provide direct evidence to suggest MDSCs as new target of curcumin for cancer prevention. The results of the study will provide useful information that will facilitate to develop more effective chemoprevention approaches for human gastric cancer.